This invention relates generally to methods and pharmaceutical formulations for treating warts, particularly cutaneous non-genital warts caused by the human papilloma virus. More particularly, this invention relates to the use of a pharmacologically active base in such methods and formulations.
Warts are benign protuberances of the skin or mucosa that are caused by the human papilloma virus (HPV). They represent one of the most common skin diseases, affecting approximately 7-12% of the world population. Warts occur most commonly on the hands and feet but can affect nearly any area of skin or mucosal surface. Children are the most commonly afflicted, with the incidence dropping significantly after the age of 25; warts can, however, occur at any age. Although rarely medically serious, warts nevertheless are cosmetically disfiguring, and patients will expend considerable time and resources to remove them. Warts on the soles of the feet (plantar warts) can be painful and interfere with walking. Rarely, non-genital HPV infections will induce cancer.
Genital warts are warts that affect the anogenital regions of both males and females, including the vagina and cervix, and represent the most common sexually transmitted viral disease worldwide. Unlike the case with non-genital warts, when some varieties of HPV affect the anogenital region they produce carcinomas at moderate to high frequencies. These carcinomas can affect the genitals, anus, cervix, and lower bowel, and can lead to metastatic cancers and significant mortality. Although the present invention relates primarily to the treatment of non-genital warts, external cutaneous genital warts can also be treated by the methods and compositions of this invention.
Etiology and Varieties:
The causative agent of warts, HPV, is a DNA virus of the papovavirus group. More than 75 varieties of HPV have been described; these are referred to by their type numbers (e.g., HPV type 6). Certain types are found more commonly at certain anatomical sites, but warts caused by any HPV type may be found at any location on the skin or mucosa.
All warts result from HPV that penetrates and infects the epithelium, in which it remains confined. Infection is through contact with an infected individual or with an object touched by an infected individual. An infected individual may spread warts to uninfected areas of the body through scratching or rubbing existing warts and then touching other areas of skin or mucosa (autoinnoculation). The virus enters the skin or mucus membrane through cuts, abrasions, or other surface disruptions. In the skin the virus replicates primarily in the upper layers of the epidermis in differentiated cells. Following a latency period of several months, and less commonly as much as several years, tiny protuberances appear in the affected area. In the skin, these are hyperkeratotic lesions. The protuberances slowly grow and, in the most common form, result in grayish, rough, rounded structures, though other varieties distinguished by shape and color also occur.
Many descriptive terms have been used in attempts to categorize warts; some of the recognized varieties of non-genital warts are as follows:
Common warts (verruca vulgaris): These are hard, roughly circular papules ranging in size from less than one millimeter to greater than one centimeter across. Their surface is generally rough and commonly fissured or scaly. Less frequently, they may have a more complex branched or cauliflower-like structure. Two or more papules that are close together sometimes coalesce. Common warts occur most frequently on the hands, somewhat less so on the knees, and occur less frequently elsewhere. They are sometimes spread to the mouth and tongue by biting of the fingernails, around which warts commonly occur. Available data indicate that HPV types 1, 2, 4, 7, and less commonly types 3, 27, 29, and 57, are associated with common warts.
Filiform warts (verruca filiformis): These are long, thin, sometimes threadlike growths. They occur most commonly on the face, particularly on the eyelids, scalp, lips, or nares.
Flat or planar warts (juvenile warts; verruca plana juvenilis): Flat warts are smoother and less elevated than common warts. They tend to be multiple and abundant, sometimes forming large groups of coalescing lesions. They may occur along a scratch or other site of trauma (Koebner phenomenon). While flat warts may occur anywhere, they are most common on the face, forehead, hands, and shins. HPV types 3, 10, 28, and possibly 41 appear to be most frequently associated with flat warts.
Myrmecia warts: These warts are characterized by their deep extension into the skin, where they tend to cause more inflammation and pain than other varieties of warts. On the surface they are generally round and dome shaped. They occur mostly on the soles of the feet (plantar warts), the palms, around or under the nails, or less commonly on the face or elsewhere. Myrmecia warts are histologically characterized by an abundance of eosinophilic inclusions. These warts appear to be caused mainly by HPV type 1, and less commonly by HPV types 2, 3, 4, 27, 29, and 57.
Plantar warts (verruca plantaris): Plantar warts occur anywhere on the soles of the feet, but particularly on weight-bearing portions, such as the heel and over the metatarsal heads. These warts commonly occur in groups, which are sometimes called mosaic warts. Plantar warts are often of the myrmecia variety and can be very painful, interfering with the ability to walk. Plantar warts appear to be most commonly associated with HPV types 1, 2, and 4.
Butcher""s warts: These warts generally resemble common warts, but with a greater tendency to form complex branched and cauliflower-like structures. They are particularly common around the fingernails. As the name suggests, this variety is found mostly in people who handle raw meat frequently. It appears to be caused predominately by HPV types 7 and 10.
Cystic warts: These occur as nodules on the weight bearing parts of the sole. Of uncertain etiology, a cystic wart appears to be either a cyst that has become secondarily infected with HPV, or an epidermal HPV infection that has migrated into the dermis, becoming an epidermal inclusion cyst. Cystic warts appear to be associated with HPV type 60.
Epidermodysplasia verruciformis: This is a rare disorder that apparently results from a congenital defect affecting the immune response to HPV. Patients develop widespread common and flat warts in childhood that generally never regress. A significant number of patients, perhaps 30 to 80 percent, develop associated squamous cell carcinoma, particularly in areas exposed to sunlight or x-rays. Many HPV types have been found associated with this disorder; types 5, 8, and possibly 14, 17, and 20 appear particularly associated with malignancy.
Current Treatments:
Warts are currently treated mainly with topical agents or by cryosurgery. Less commonly, they are treated with intralesional injections, systemic medication, laser surgery, electrodessication and curettage, or surgical excision. Further details on some of these methods follow:
Topical treatments: Most compositions used as topical treatments for warts are keratolytic; that is, they break down keratin and desquamate the tissue. Most of the compounds are irritants and some are directly necrotic. The most commonly used topical preparations are those containing salicylic acid. These have long been used to treat cutaneous warts, particularly common warts. A solution containing salicylic acid, and sometimes lactic acid or other ingredients, is applied daily to the warts. The treated areas may be kept covered with a bandage or other occlusive material. Desquamation and peeling of the tissue occurs, and eventually the wart is reduced in size and may ultimately regress completely. The treatment generally takes several weeks. Salicylic acid has the advantages of being available without a prescription, being applicable at home, and having relatively low toxicity. Disadvantages are that it can damage healthy skin, it is often not entirely effective so that recurrences are frequent, and secondary infections may arise in the treatment-damaged skin.
Several other topical agents have also been used; many of these are available only by prescription and many must be applied by medical professionals. Dinitrochlorobenzene is a strong skin irritant that induces dermatitis and an immune response; it may also be a mutagen and must be used with caution. Cantharidin, derived from the blister beetle (also known as the Spanish fly), causes necrosis and blistering of the skin. Multiple applications are usually required; scarring, damage to healthy skin, spread of HPV infection, and secondary infections may occur with treatment. Trichloroacetic acid preparations cause similar reactions and have similar problems. Podophyllin preparations are strong skin irritants that must be used cautiously as they can cause significant systemic adverse effects and are contraindicated during pregnancy; they are used mainly for treating genital warts and, less commonly, for treating plantar warts. Imiquimod, cidofovir, podophyllotoxin, 5-fluorouracil, and tretinoin are prescription drugs that have been tried as topical treatments for warts. Imiquimod is a proinflammatory agent that is used mainly for treating genital warts but may have some use in treating common warts; efficacy data are presently very limited. Cidovir is an antiviral agent that may be useful against warts; it is currently expensive and efficacy data are very limited. 5-Fluorouracil is an anticancer drug that is occasionally used on warts, particularly flat warts; it must be used under occlusion daily for several weeks. Side effects include hyperpigmentation and skin erosion, and it is contraindicated during pregnancy. Tretinoin (all-trans-retinoic acid), used to treat acne, has shown some efficacy in treating warts through daily treatment for several weeks, often in combination with other skin irritants. This compound is a teratogen and is rarely administered to women of childbearing age.
Cryotherapy: This method uses liquid nitrogen or another cold material to freeze the wart tissue. The procedure usually must be repeated every one to four weeks for approximately three months. Pain, blistering, scarring, secondary infection, nerve damage, ulceration, and pigment changes may occur.
Intralesional injections: When other methods have failed, intralesional injections are sometimes used to treat warts. Bleomycin and alpha-interferon have both been tried. Bleomycin is highly toxic, commonly painful, and often ineffective. Alpha interferon treatments last weeks to months, are mildly toxic, and have modest efficacy at best.
Systemic medications: Systemic medications are used only in cases of abundant and recalcitrant warts. Available evidence shows that in non-immunocompromised patients systemic medications are rarely effective. Systemic retinoids have shown some efficacy in treating extensive and painful warts in some immunocompromised patients.
Electrodessication and curettage: This technique is used infrequently as it is painful, commonly causes scarring, and puts HPV particles into the air.
Laser surgery: Warts can be removed with laser surgery, but the procedure is painful, leaves scars, and may spread HPV through the air.
Surgical excision: This technique is rarely used, as scarring and recurrence are common.
As most warts will spontaneously resolve within two years, judging the efficacy of any of these interventions is not always clear. A recent survey of clinical trial results for local cutaneous wart treatments (Cochrane Database Syst. Rev. 2:CD001781, 2001) found simple topical treatments containing salicylic acid to have the highest cure rates (about 75% vs 48% for placebos). Cryotherapy had cure rates ranging from no better than placebo to no better than salicylic acid. Topical dinitrochlorobenzene was concluded to have modest efficacy at best, though with significant toxicity. Evidence for the efficacy of topical 5-fluorouracil, intralesional bleomycin or interferons, and photodynamic therapy was concluded to be weak at best, and all of these therapies are potentially toxic or otherwise hazardous.
Existing treatments for warts are thus of limited efficacy, have high risks for adverse effects, are commonly irritating or otherwise painful, or are time consuming and inconvenient for the patient. It has now been discovered that certain basic compositions, when used as described herein, successfully treat warts without the pain, irritation, and other adverse effects experienced with other treatments for warts. The present invention provides a novel treatment for warts that is effective, safe, not painful, and convenient.
It is accordingly a primary object of the invention to address the above needs in the art by providing a novel method and formulation for the treatment of warts, particularly non-genital cutaneous warts.
The invention provides a method and formulation for the treatment of warts that involves a topically applied formulation containing a pharmacologically active base in an amount effective to provide the formulation with a pH in the range of about 7.5 to 13.0. The formulation may be a lotion, cream, solution, paste, ointment, plaster, paint, bioadhesive, or the like, or may be contained in a tape or in a skin patch comprised of a laminated composite intended for long-term adhesion to the body surface (typically throughout a delivery period in the range of about 8 to about 72 hours) in the affected area.